U.S. patent number 5,185,352 [Application Number 07/640,407] was granted by the patent office on 1993-02-09 for alkoxy-4(1h)-pyridone derivatives, processes for the preparation thereof and pharmaceutical compositions containing them.
This patent grant is currently assigned to Goedecke Aktiengesellschaft. Invention is credited to Julian Aranda, Johannes Hartenstein, Hartmut Osswald, Reinhard Reck, Claus Rudolph, Christopher Schachtele, Gunter Weinheimer.
United States Patent |
5,185,352 |
Aranda , et al. |
February 9, 1993 |
Alkoxy-4(1H)-pyridone derivatives, processes for the preparation
thereof and pharmaceutical compositions containing them
Abstract
The invention concerns new derivatives of certain alkoxy
-4(1H)-pyridones, processes for preparing them, and pharmaceutical
compositions containing them. The compounds of the invention are
useful in the prevention and/or treatment of heart and blood vessel
diseases such as thromboses, arteriosclerosis and hypertension, and
of inflammatory processes, allergies, cancers, and certain
degenerative damage of the central nervous system.
Inventors: |
Aranda; Julian (Vorstetten,
DE), Hartenstein; Johannes (Stegen-Wittental,
DE), Reck; Reinhard (Sexau, DE),
Schachtele; Christopher (Freiburg, DE), Rudolph;
Claus (Vorstetten, DE), Osswald; Hartmut
(Emmendingen, DE), Weinheimer; Gunter (Denzlingen,
DE) |
Assignee: |
Goedecke Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
6360419 |
Appl.
No.: |
07/640,407 |
Filed: |
January 28, 1991 |
PCT
Filed: |
August 04, 1989 |
PCT No.: |
PCT/EP89/00927 |
371
Date: |
January 28, 1991 |
102(e)
Date: |
January 28, 1991 |
PCT
Pub. No.: |
WO90/01477 |
PCT
Pub. Date: |
February 22, 1990 |
Foreign Application Priority Data
Current U.S.
Class: |
514/348;
514/253.12; 544/365; 546/194; 549/292; 544/360; 544/295; 544/131;
514/318; 514/235.5; 546/296; 546/193 |
Current CPC
Class: |
C07D
213/69 (20130101); A61P 7/02 (20180101); A61P
9/10 (20180101); A61P 9/12 (20180101); A61P
37/08 (20180101); A61P 43/00 (20180101); C07D
401/06 (20130101); A61P 35/00 (20180101) |
Current International
Class: |
C07D
213/00 (20060101); C07D 213/69 (20060101); C07D
401/00 (20060101); C07D 401/06 (20060101); C07D
213/69 (); C07D 401/06 (); C07D 309/30 (); A61K
031/44 () |
Field of
Search: |
;546/296 ;514/348 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
55-4715 |
|
Mar 1958 |
|
CA |
|
978958 |
|
Dec 1975 |
|
CA |
|
0120670 |
|
Mar 1984 |
|
EP |
|
110674 |
|
Jun 1984 |
|
JP |
|
110675 |
|
Jun 1984 |
|
JP |
|
Other References
Imafuru et al., Bulletin of the Chemical Socity of Japan, vol. 52,
No. 1, 1979, pp. 107-110. .
Looker et al., Journal of Heterocyclic Chemistry, vol. 23, No. 5,
1986, pp. 5-8..
|
Primary Examiner: Shah; Harold J.
Assistant Examiner: Bernhardt; F.
Attorney, Agent or Firm: Anderson; Elizabeth M.
Claims
We claim:
1. A compound of formula ##STR22## or a pharmaceutically acceptable
salt thereof wherein R.sup.1 is straight or branched, saturated or
unsaturated alkyl of from 10 to 22 carbon atoms or adamantylalkyl
of from 1 to 22 carbon atoms;
R.sup.2 is a straight or branched, saturated or unsaturated alkyl
of from 1 to 5 carbon atoms, a cycloalkylmethyl radical having 5 to
7 carbon atoms in the cycloalkyl ring, phenyl, phenylalkyl with 1
to 5 carbon atoms in the straight or branched alkyl chain which
phenyl ring is unsubstituted or substituted by halogen, hydroxyl,
alkyl of from 1 to 5 carbon atoms, alkoxy of from 1 to 5 carbon
atoms, dialkylamino having of from 1 to 5 carbon atoms,
benzyloxy;
n is an integer of from 1 to 5; and
R.sup.3 is selected from
a) halogen, hydroxyl, cyano, carboxamido, alkoxycarbonyl having 1
to 5 carbon atoms in the alkyl moiety or amino of formula ##STR23##
wherein R.sup.6 and R.sup.7, which are each independently hydrogen,
alkyl or omegahydroxyalkyl of from 1 to 5 carbon atoms, phenyl,
phenylalkyl with from 1 to up to 5 carbon atoms in the straight or
branched alkyl which phenyl ring is unsubstituted or substituted by
halogen, hydroxyl, alkyl of from 1 to 5 carbon atoms, alkoxy of
from 1 to 5 carbon atoms, dialkylamino of from 1 to 5 carbon atoms,
or benzyloxy;
b) ##STR24## wherein R.sup.8 is hydrogen or alkyl of from 1 to 5
carbon atoms, R.sup.9 and R.sup.10 are each independently hydrogen,
alkyl of from 1 to 5 carbon atoms, phenyl, phenylalkyl with from 1
to 5 carbon atoms in the straight or branched alkyl chain such
phenyl ring is unsubstituted or substituted by halogen, hydroxyl,
alkyl of from 1 to 5 carbon atoms, alkoxy of from 1 to 5 carbon
atoms, dialkylamino of from 1 to 5 carbon atoms, benzyloxy; and k
is an integer of from 2 to 5;
and
c) ##STR25## wherein R.sup.9 and R.sup.10 have the above-given
meanings and r is an integer of from 2 to 5.
2. A compound of formula ##STR26## of a pharmaceutically acceptable
salt thereof wherein R.sup.1 is a straight or branched, saturated
or unsaturated alkyl of from 10 to 22 carbon atoms or
adamantylalkyl having from 1 to 22 carbon atoms;
R.sup.2 is a straight or branched alkyl having from 1 to 4 carbon
atoms, cyclohexylmethyl, unsubstituted phenyl, phenylalkyl with
from 1 to 5 carbon atoms in the straight or branched alkyl chain
which phenyl is monosubstituted by halogen, hydroxyl, methyl,
benzyloxy, methoxy or dimethylamino;
n is an integer of from 1 to 3; and
R.sup.3 is selected from
a) halogen, hydroxyl, cyano, carboxamido, alkoxycarbonyl of from 1
to 5 carbon atoms in the alkyl moiety or a radical of formula III,
in which R.sup.6 and R.sup.7 are each independently hydrogen,
methyl, omega-hydroxypropyl or benzyl;
b) a radical of formula IV, in which R.sup.8 is hydrogen or methyl,
R.sup.9 and R.sup.10 are each independently hydrogen, methyl,
benzyl, or phenylethyl and k is 2, 3 or 4;
c) formula ##STR27## in which R.sup.9 and R.sup.10 are each methyl
and r is 2 or 3.
3. A compound of formula ##STR28## or a pharmaceutically acceptable
salt thereof wherein n is 1, 2 or 3;
R.sup.1 is decyl, tetradecyl, eicosanyl, octadecenyl, octadecyl,
2-octyldecyl or adamantylethyl;
R.sup.2 is a propyl, methyl, phenyl, benzyl, methylbenzyl,
chlorobenzyl, methoxybenzyl, cyclohexylmethyl, dimethylaminobenzyl,
dimethylaminopropyl, benzyloxybenzyl, benzyloxyphenyl, phenylethyl,
hydroxybenzyl or hydroxyphenyl; and
R.sup.3 is bromine, hydroxy, cyano, amino, carboxamido,
methoxycarbonyl, dimethylaminopropylamino,
dimethylaminopropyl-N-methylamino, hydroxypropylamino,
dimethylamino-N-methylamino, aminopropylamino, aminoethylamino,
aminobutylamino, dimethylamino, dimethylaminopropoxy,
N-benzyl-N-methylaminopropylamino, N-benzyl-N-methylamino.
4. A compound selected from
1-Benzyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-Benzyl-5-butoxy-2-hydroxymethyl-4(1H)-pyridone,
1-Benzyl-5-decyloxy-2-hydroxymethyl-4(1H)-pyridone,
1-Benzyl-2-hydroxymethyl-5-tetradecyloxy-4(1H)-pyridone,
1-Benzyl-5-eicosanyloxy-2-hydroxymethyl-4(1H)-pyridone,
1-Benzyl-2-hydroxymethyl-5-(9-cis-octadecenyloxy-4(1H)-pyridone,
2-Hydroxymethyl-1-(4-methylbenzyl)-5-octadecyloxy-4(1H)-pyridone,
1-(4-Chlorobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
2-Hydroxymethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone,
2-Hydroxymethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone,
1-Cyclohexylmethyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(4-Dimethylaminobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(3-Dimethylaminopropyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(4-Benzyloxybenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-Benzyl-2-hydroxymethyl-5-(2-octyldecyloxy)-4(1H)-pyridone,
and
5-[2-(1-Adamantyl)ethoxy]-1-benzyl-2-hydroxymethyl-4(1H)-pyridone.
5. A compound selected from
(.+-.)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
(-)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
(+)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
2-Hydroxymethyl-5-octadecyloxy-1propyl-4(1H)-pyridone,
2-Hydroxymethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone,
2-Hydroxymethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone, and
1-(4-Benzyloxyphenyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone.
6. A compound selected from
1-Benzyl-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
1-Benzyl-2-bromomethyl-5-butoxy-4(1H)-pyridone hydrobromide,
1-Benzyl-2-bromomethyl-5-decyloxy-4(1H)-pyridone hydrobromide,
1-Benzyl-2-bromomethyl-5-tetradecyloxy-4(1H)-pyridone
hydrobromide,
1-Benzyl-2-bromomethyl-5-eicosanyloxy-4(1H)-pyridone
hydrobromide,
1-Benzyl-2-bromomethyl-5-(9-cis-octadecenyloxy)-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-(4-methylbenzyl)-5-octadecyloxy)-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-(4-chlorobenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-cyclohexylmethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-(4-dimethylaminobenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-5-octadecyloxy-1-propyl-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-Bromomethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone
hydrobromide,
1-(4-Benzyloxybenzyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide, and
1-(4-Benzyloxyphenyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide.
7. A compound selected from
1-Benzyl-2-bromomethyl-5-(2-octyldecyloxy)-4(1H)-pyridone.multidot.hydrobro
mide,
5-[2-(1-Adamantyl)ethoxy]-1-benzyl-2-bromomethyl-4(1H)-pyridone.multidot.hy
drobromide,
(.+-.)-2-Bromomethyl-5-octadecycloxy-1-(1-phenylethyl)-4(1H)-pyridone.multi
dot.hydrobromide,
(-)-2-Bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multidot.
hydrobromide, and
(+)-2-Bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multidot.
hydrobromide.
8. A compound selected from
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-4(1H)-pyri
done dioxalate,
1-Benzyl-2-[N-(3-hydroxypropyl)-aminomethyl]-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-Dimethylaminopropyl)-aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyr
idone trihydrochloride hemihydrate,
1-Benzyl-2-[N-(2-dimethylaminoethyl)-N-methylaminomethyl]-5-octadecyloxy-4(
1H)-pyridone trihydrochloride,
2-[N-(3-Hydroxypropyl)aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-5octadecyloxy-1propyl-4(1H)-pyrido
ne dioxalat,
2-[N-(3-Aminopropyl)-aminomethyl]-1methyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
2-[N-(3-Aminopropyl)-aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
2-[N-(3-Aminopropyl)aminomethyl]-1propyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
1-Benzyl-5-butyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate 3/4 hydrate,
1-Benzyl-5-decyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate hemihydrate,
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-tetradecyloxy-4(1H)-pyr
idone dioxalate monohydrate,
1-Benzyl-2[N-(3-dimethylaminopropyl)aminomethyl]-5-eicosanyloxy-4(1H)-pyrid
one dioxalate monohydrate,
2-[N-(2-Aminoethyl)aminomethyl]-1benzyl-5-octadecyloxy-4(1H)-pyridone
1/4 hydrate,
1-Cyclohexylmethyl-2-[N-(3-dimethylaminopropyl)-aminomethyl]-5-octadecyloxy
-4(1H)-pyridone difumarate,
1-(4-Chlorobenzyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-
4(1H)-pyridone difumarate 1.25 hydrate,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-5-octadecyloxy-1-phenyl-4(1H)-pyri
done; diisopropyl ether,
1-Benzyl-2-[N-(3-N-benzyl-N-methylaminopropyl)-aminomethyl]-5-octadecyloxy-
4(1H)-pyridone difumarate,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone trihydrochloride monohydrate,
1-Benzyl-2-dimethylaminomethyl-5-octadecyloxy-4(1H)-pyridone
oxalate hemihydrate,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(2-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone difumarate,
1-Benzyl-2-(N-benzyl-N-methylaminomethyl)-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-methylbenzyl)-5-octadecyloxy-
4(1H)-pyridone trihydrochloride hemihydrate,
2-[N-(4-Aminobutyl)aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
1Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(9-cis-octadecenyloxy)-4
(1H)-pyridone.multidot.trihydrochloride.multidot.1/2 H.sub.2 O,
1-(4-Benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone,
1-(4-Benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone.multidot.difumarate.multidot.2,5 H.sub.2 O,
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(2-octyldecyloxy)-4(1H)
-pyridone.multidot.trihydrochloride.multidot.3/4 H.sub.2 O,
5-(2Adamantylethoxy)-1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H
)-pyridone, and
(.+-.)-1-Benzyl-5-octadecyloxy)-2{N-([3-(1-phenylethyl)aminopropyl]aminomet
hyl}-4(1H)-pyridone.multidot.trihydrochloride.
9. A compound selected from:
1-Benzyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-pyridone
dihydrochloride,
2-(3-Dimethylaminopropoxymethyl)-1-methyl-5-octadecyloxy-4(1H)-pyridone
dihydrochloride,
2-(3-Dimethylaminopropoxymethyl)-5-octadecyloxy-1-propyl-4(1H)-pyridone
dihydrochloride 3/4 hydrate,
2-(3-Dimethylaminopropoxymethyl)-1(4-methylbenzyl)-5-octadecyloxy-4(1H)-pyr
idone dihydrochloride sesquihydrate,
2-(3-Dimethylaminopropoxymethyl)-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone dihydrochloride 1/4 hydrate,
1-Cyclohexylmethyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone oxalate,
1-(4-Chlorobenzyl)-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone dihydrochloride 2.5 hydrate,
2-(3-Dimethylaminopropoxymethyl)-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone sesquihydrate,
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile hydrochloride,
3-(1-Methyl-5-octadecyloxy-4(1H)-pyridon-2-yl)-propionic acid
nitrile,
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propylamine
dihydrochloride,
Methyl
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionate,
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propanol, and
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
amide.
10. A compound selected from
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-hydroxybenzyl)-5-octadecyloxy
-4(1H)-pyridone.multidot.dihydrochloride.multidot.2 H.sub.2 O,
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4hydroxyphenyl)-5-octadecyloxy-
4(1H)-pyridone.multidot.trihydrochloride.multidot.0,5 H.sub.2 O,
and
1-Benzyl-2-[N-(3-dimethylaminopropyl)-N-methylaminomethyl]-5-octadecyloxy-4
(1H)-pyridone trihydrochloride.
11. A pharmaceutical composition for treating and/or preventing
heart and blood vessel diseases comprising an effective amount of a
compound according to claim 1 in admixture with a pharmaceutically
acceptable carrier.
12. A method for treating and/or preventing heart and blood vessel
diseases which comprises administering to a mammal in need of such
treatment a pharmaceutical composition according to claim 11.
Description
BACKGROUND OF THE INVENTION
The compounds of formula I according to the present invention
display useful pharmacological properties. In particular, they
inhibit protein kinase C, a calcium- and phospholipid-dependent key
enzyme, which plays a decisive part in the intracellular signal
chain transduction (Y. Nishizuka, Science, 233, 305-312/1986) and
is closely linked with the regulation of contractile, secretory and
proliferative processes.
SUMMARY OF THE INVENTION
The invention concerns compounds of formula ##STR1## and
pharmaceutically acceptable salts thereof wherein R.sup.1, R.sup.2,
R.sup.3, and n are as described below.
The preferred compounds of the invention are those of formula I
wherein
R.sup.1 is a straight or branched, saturated or unsaturated alkyl
of from 1 to 22 carbon atoms or adamantylalkyl containing from 1 to
22 carbon atoms;
R.sup.2 is a straight or branched alkyl containing from 1 to 4
carbon atoms, cyclohexylmethyl, unsubstituted phenyl, phenylalkyl
with from 1 to 5 carbon atoms in the straight or branched alkyl
chain in which the phenyl ring is monosubstituted by halogen,
hydroxyl, methyl, benzyloxy, methoxy or dimethylamino;
n is an integer of from 1 to 3; and
R.sup.3 is selected from
a) halogen, hydroxyl, cyano, carboxamido alkoxycarbonyl of from 1
to 5 carbon atoms in the alkyl moiety or a radical of formula III,
in which R.sup.6 and R.sup.7, which are each independently
hydrogen, methyl, omegahydroxypropyl or benzyl;
b) a radical of formula IV, in which R.sup.8 is hydrogen or methyl,
R.sup.9 and R.sup.10 are each independently hydrogen, methyl,
benzyl or phenylethyl and k is 2, 3 or 4;
c) formula V in which R.sup.11 and R.sup.12, are each independently
hydrogen or methyl, X is an amino radical of formula VI, in which
R.sup.13 is hydrogen, phenyl, phenylalkyl or diphenylalkyl with
from 1 to 5 carbon atoms in the straight or branched alkyl chain
and where from 1 to 3 CH-groups in the phenyl ring are substituted
by nitrogen or X is formula VII, in which R.sup.14 is phenyl,
R.sup.15 is cyano or aminomethyl, and p and q are each 2; and
d) formula VIII, in which R.sup.9 and R.sup.10 are each methyl and
r is 2 or 3.
More preferred compounds of the invention are those of formula I
wherein
n is 1, 2 or 3;
R.sup.1 is a decyl, tetradecyl, eicosanyl, octadecenyl, octadecyl,
2-octyldecyl or adamantylethyl;
R.sup.2 is propyl, methyl, phenyl, benzyl, methylbenzyl,
chlorobenzyl, methoxybenzyl, cyclohexylmethyl, dimethylaminobenzyl,
dimethylaminopropyl, benzyloxybenzyl, benzyloxyphenyl, phenylethyl,
hydroxybenzyl or hydroxyphenyl; and
R.sup.3 is bromine, hydroxy, cyano, amino, carboxamido,
methoxycarbonyl, dimethylaminopropylamino,
dimethylaminopropyl-N-methylamino, hydroxypropylamino,
dimethylamino-N-methylamino, aminopropylamino, aminoethylamino,
aminobutylamino, dimethylamino, dimethylaminopropoxy,
N-benzyl-N-methylaminopropylamino, N-benzyl-N-methylamino,
methoxycarbonylmethylpiperazino, benzylpiperazino,
diphenylmethylpiperazino, aminomethylphenylpiperidino,
phenylpiperazino, phenylethylpiperazino, pyrimidinylpiperazino or
methylpiperazino.
Useful intermediate for preparing compounds of the instant
invention include:
2-hydroxymethyl-5-octadecyloxy-4-pyranone,
2-hydroxymethyl-5-tetradecyloxy-4-pyranone,
5-eicosanyloxy-2-hydroxymethyl-4-pyranone,
5-butyloxy-2-hydroxymethyl-4-pyranone,
5-decyloxy-2-hydroxymethyl-4-pyranone,
2-hydroxymethyl-5-(9-cis-octadecenyloxy)-4-pyranone,
2-hydroxymethyl-5-(2-octyldecyloxy)-4-pyranone,
5-[2-(1-adamantyl)ethoxy]-2-hydroxymethyl-4-pyranone,
Still more preferred compounds of the instant invention are:
1-benzyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-benzyl-5-butoxy-2-hydroxymethyl-4(1H)-pyridone,
1-benzyl-5-decyloxy-2-hydroxymethyl-4(1H)-pyridone,
1-benzyl-2-hydroxymethyl-5-tetradecyloxy-4(1H)-pyridone,
1-benzyl-5-eicosanyloxy-2-hydroxymethyl-4(1H)-pyridone,
1-benzyl-2-hydroxymethyl-5-(9-cis-octadecenyloxy)-4(1H)-pyridone,
2-hydroxymethyl-1-(4-methylbenzyl)-5-octadecyloxy-4(1H)-pyridone,
1-(4-chlorobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
2-hydroxymethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone,
2-hydroxymethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone,
1-cyclohexylmethyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(4-dimethylaminobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(3-dimethylaminopropyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-(4-benzyloxybenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-benzyl-2-hydroxymethyl-5-(2-octyldecyloxy)-4(1H)-pyridone,
5-[2-(1-adamantyl)ethoxy]-1-benzyl-2-hydroxymethyl-4(1H)-pyridone,
(.+-.)-2-hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
(-)-2-hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
(+)-2-hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
2-hydroxymethyl-5-octadecyloxy-1-propyl-4(1H)-pyridone,
2-hydroxymethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone,
2-hydroxymethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone,
1-(4-benzyloxyphenyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone,
1-benzyl-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
1-benzyl-2-bromomethyl-5-butoxy-4(1H)-pyridone hydrobromide,
1-benzyl-2-bromomethyl-5-decyloxy-4(1H)-pyridone hydrobromide,
1-benzyl-2-bromomethyl-5-tetradecyloxy-4(1H)-pyridone
hydrobromide,
1-benzyl-2-bromomethyl-5-eicosanyloxy-4(1H)-pyridone
hydrobromide,
1-benzyl-2-bromomethyl-5-(9-cis-octadecenyloxy)-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-(4-methylbenzyl)-5-octadecyloxy)-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-(4-chlorobenzyl)-5-octadecyloxy)-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-cyclohexylmethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-(4-dimethylaminobenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-bromomethyl-5-octadecyloxy-1-propyl-4(1H)-pyridone
hydrobromide,
2-bromomethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
2-bromomethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone
hydrobromide,
1-(4-benzyloxybenzyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
1-(4-benzyloxyphenyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide,
1-benzyl-2-bromomethyl-5-(2-octyldecyloxy)-4(1H)-pyridone.multidot.hydrobro
mide,
5-[2-(1-adamantyl)ethoxy]-1-benzyl-2-bromomethyl-4(1H)-pyridone.multidot.hy
drobromide,
(.+-.)-2-bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multid
ot.hydrobromide,
(-)-2-bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multidot.
hydrobromide,
(.+-.)-2-bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multid
ot.hydrobromide,
1-benzyl-2-[N-(3-dimethylaminopropyl)-aminomethyl]-5-octadecyloxy-4(1H)-pyr
idone dioxalate,
1-benzyl-2-[N-(3-hydroxypropyl)-aminomethyl]-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-dimethylaminopropyl)-aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyr
idone trihydrochloride hemihydrate,
1-benzyl-2-[N-(2-dimethylaminoethyl)-N-methylaminomethyl]-5-octadecyloxy-4(
1H)-pyridone trihydrochloride,
2-[N-(3-hydroxypropyl)aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-1-propyl-4(1H)-pyri
done dioxalat,
2-[N-(3-aminopropyl)-aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
2-[N-(3-aminopropyl)-aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
2-[N-(3-aminopropyl)aminomethyl]-1-propyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
1-benzyl-5-butyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate 3/4 hydrate,
1-benzyl-5-decyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate hemihydrate,
1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-tetradecyloxy-4(1H)-pyr
idone dioxalate monohydrate,
1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-eicosanyloxy-4(1H)-pyri
done dioxalate monohydrate,
2-[N-(2-aminoethyl)aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
1/4 hydrate,
1-cyclohexylmethyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-
4(1H)-pyridone difumarate,
1-(4-chlorobenzyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-
4(1H)-pyridone difumarate 1.25 hydrate,
2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-1-phenyl-4(1H)-pyri
done; diisopropyl ether,
1-benzyl-2-[N-(3-N-benzyl-N-methylaminopropyl)aminomethyl]-5-octadecyloxy-4
(1H)-pyridone difumarate,
2-[N-(3-dimethylaminopropyl)aminomethyl]-1-(4-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone trihydrochloride monohydrate,
1-benzyl-2-dimethylaminomethyl-5-octadecyloxy-4(1H)-pyridone
oxalate hemihydrate,
2-[N-(3-dimethylaminopropyl)aminomethyl]-1-(2-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone difumarate,
1-benzyl-2-(N-benzyl-N-methylaminomethyl)-5-octadecyloxy-4(1H)-pyridone,
2-[N-(3-dimethylaminopropyl)aminomethyl]-1-(4-methylbenzyl)-5-octadecyloxy-
4(1H)-pyridone trihydrochloride hemihydrate,
2-[N-(4-aminobutyl)aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride,
1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(9-cis-octadecenyloxy)-
4(1H)-pyridone.multidot.trihydrochloride.multidot.1/2H.sub.2 O,
1-(4-benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone,
1-(4-benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone.multidot.difumarate.multidot.2,5 H.sub.2 O,
1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(2-octyldecyloxy)-4(1H)
-pyridone.multidot.trihydrochloride.multidot.3/4 H.sub.2 O,
5-(2-adamantylethoxy)-1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1
H)-pyridone,
(.+-.)-1-benzyl-5-octadecyloxy)-2-{N-[3-(1-phenylethyl)aminopropyl]aminomet
hyl}-4(1H)-pyridone.multidot.trihydrochloride,
2-[N-(3-dimethylaminopropyl)aminomethyl]-1-(4-hydroxybenzyl)-5-octadecyloxy
-4(1H)-pyridone.multidot.dihydrochloride.multidot.2 H.sub.2 O,
2-[N-(3-dimethylaminopropyl)aminomethyl]-1-(4-hydroxyphenyl)-5-octadecyloxy
-4(1H)-pyridone.multidot.trihydrochloride.multidot.0,5 H.sub.2
O,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-cyano-4-phenylpipe
ridine dihydrochloride,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-methoxycarbonyl-2-
methyl-piperazine dihydrochloride 3/4 hydrate,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-benzylpiperazine,
1-benzyl-2-[N-(3-dimethylaminopropyl)-N-methylaminomethyl]-5-octadecyloxy-4
(1H)-pyridone trihydrochloride,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-diphenylmethylpipe
razine sesquioxalate monohydrate,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-phenylpiperazine.
multidot.dihydrochloride.multidot.H.sub.2 O,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-(2-pyrimidinyl)pi
perazine,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-benzylpiperazine.
multidot.dioxalate.multidot.1/2 H.sub.2 O,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-(2-phenylethyl)pi
perazine.multidot.trihydrochloride.multidot.1/2 H.sub.2 O,
1-[(1-benzyl-5-decyloxy-4(1H)-pyridone-2-yl)methyl]-4-(2-phenylethyl)pipera
zine.multidot.dihydrochloride,
1-[(1-benzyl-5-benzyloxy-4(1H)-pyridone-2-yl)methyl]-4-benzylpiperazine.mul
tidot.trihydrochloride,
(.+-.)-1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-(1-phenyle
thyl)piperazine.multidot.trihydrochloride 3/4 H.sub.2 O,
(.+-.)-1-[(5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone-2-yl)methyl]-4-b
enzylpiperazine,
(-)-1-[(5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone-2-yl)methyl]-4-benz
ylpiperazine,
(+)-1-[(5-octadecyloxy-1-(1-phenylethyl)4(1H)-pyridone-2-yl)methyl]-4-benzy
lpiperazine,
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-aminomethyl-4-phen
ylpiperidine trihydrochloride,
(.+-.)-1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-2-methylpiper
azine fumarate,
1-benzyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-pyridone
dihydrochloride,
2-(3-dimethylaminopropoxymethyl)-1-methyl-5-octadecyloxy-4(1H)-pyridone
dihydrochloride,
2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-1-propyl-4(1H)-pyridone
dihydrochloride 3/4 hydrate,
2-(3-dimethylaminopropoxymethyl)-1-(4-methylbenzyl)-5-octadecyloxy-4(1H)-py
ridone dihydrochloride sesquihydrate,
2-(3-dimethylaminopropoxymethyl)-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone dihydrochloride 1/4 hydrate,
1-cyclohexylmethyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone oxalate,
1-(4-chlorobenzyl)-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone dihydrochloride 2.5 hydrate,
2-(3-dimethylaminopropoxymethyl)-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone sesquihydrate,
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile hydrochloride,
3-(1-methyl-5-octadecyloxy-4(1H)-pyridon-2-yl)propionic acid
nitrile,
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propylamine
dihydrochloride,
methyl
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionate,
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propanol, and
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propionic acid
amide.
The invention also concerns pharmaceutical compositions for
treating and/or preventing heart and/or blood vessel diseases which
comprise a therapeutically effective amount of a compound of
formula I in admixture with a pharmaceutically acceptable
carrier.
The invention also concerns a method of treating and/or preventing
heart and blood vessel diseases such as thromboses,
arteriosclerosis, and hypertension and other diseases such as
inflammatory processes, allergies, cancers, and certain
degenerative damage to the central nervous system.
DESCRIPTION
The present invention is concerned with new alkoxy-4(1H)-pyridone
derivatives, processes for the preparation thereof and
pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
The new alkoxy-4(1H)-pyridone derivatives of the present invention
are compounds of formula ##STR2## wherein R.sup.1 is a
straight-chained or branched, saturated or unsaturated alkyl or
adamantylalkyl radical having up to 22 carbon atoms, R.sup.2 is a
straight-chained or branched, saturated or unsaturated alkyl
radical having up to 5 carbon atoms, a cycloalkylmethyl radical
having 5 to 7 carbon atoms in the cycloalkyl ring, an unsubstituted
phenyl or phenylalkyl radical with up to 5 carbon atoms in the
straight or branched alkyl chain or a phenyl or phenylalkyl radical
with up to 5 carbon atoms in the straight or branched alkyl chain
in which the phenyl ring is substituted by halogen, hydroxyl, alkyl
containing up to 5 carbon atoms, alkoxyl containing up to 5 carbon
atoms, dialkylamino containing up to 5 carbon atoms or benzyloxy or
R.sup.2 is an aminoalkyl radical of the formula ##STR3## wherein
R.sup.4 and R.sup.5, which are the same or different, are hydrogen
atoms or alkyl radicals having 1 to 3 carbon atoms and m is a whole
number of from 2 to 5, n is a whole number of from 1 to 5 and
R.sup.3 is either
a) a halogen atom, a hydroxyl, cyano or carboxamido group or an
alkoxycarbonyl radical having up to 5 carbon atoms in the alkyl
moiety or an amino group of formula ##STR4## wherein R.sup.6 and
R.sup.7, which are the same or different, are hydrogen atoms, alkyl
or omega-hydroxyalkyl radicals having up to 5 carbon atoms or
phenyl or phenylalkyl radicals with up to 5 carbon atoms in the
straight or branched alkyl chain which the phenyl ring is either
unsubstituted or substituted by halogen, hydroxyl, alkyl having up
to 5 carbon atoms, alkoxy having up to 5 carbon atoms, dialkylamino
having up to 5 carbon atoms benzyloxy; or
b) an amino radical of formula ##STR5## wherein R.sup.8 is a
hydrogen atom or an alkyl radical having up to 5 carbon atoms and
R.sup.9 and R.sup.10, which are the same or different, are hydrogen
atoms, alkyl radicals having up to 5 carbon atoms or phenyl or
phenylalkyl with up to 5 carbon atoms in the straight or branched
alkyl chain radicals which the phenyl ring is either unsubstituted
or substituted by halogen, hydroxyl, alkyl having up to 5 carbon
atoms, alkoxy having up to 5 carbon atoms, dialkylamino having up
to 5 carbon atoms or benzyloxy and k is a whole number of from 2 to
5; or
c) a heterocycle of the formula ##STR6## wherein R.sup.11 and
R.sup.12, which are the same or different, are hydrogen atoms,
alkyl radicals having up to 3 carbon atoms or phenyl or phenylalkyl
radicals with up to 5 carbon atoms in the straight or branched
alkyl chain, X is an oxygen atom, an amino group of the formula
##STR7## wherein R.sup.13 is a hydrogen atom or a phenyl,
phenylalkyl or diphenylalkyl with up to 5 carbon atoms in the
straight or branched alkyl chain and where in the phenyl ring up to
three CH-groups may be substituted by nitrogen, or a radical of
formula ##STR8## wherein R.sup.14 is a hydrogen atom or a phenyl
radical which is either unsubstituted or substituted by halogen,
hydroxyl, alkyl containing up to 5 carbon atoms, alkoxy having up
to 5 carbon atoms, dialkylamino having up to 5 carbon atoms or
benzyloxy and R.sup.15 is a hydrogen atom, a hydroxyl or cyano
group or a hydroxymethyl, aminomethyl, carboxamido, ethoxy or
methoxycarbonyl radical and p and q, which are the same or
different, signify 2 or 3; or
d) a radical of formula ##STR9## wherein R.sup.9 and R.sup.10 have
the above-given meanings and r is a whole number of from 2 to 5;
and the pharmacologically acceptable salts thereof.
Preferred compounds of the present invention are those wherein
R.sup.1 is a straight-chained or branched, saturated or unsaturated
alkyl radical containing 10 to 22 carbon atoms or an adamantylethyl
radical, R.sup.2 is a methyl, ethyl, propyl or a cyclohexylmethyl
radical, a phenyl, benzyl or phenylethyl radical which the phenyl
ring is either unsubstituted or monosubstituted by halogen,
hydroxyl, methyl, benzyloxy, methoxy or dimethylamino, or an
aminoalkyl radical of the general formula II, wherein R.sup.4 and
R.sup.5 is a methyl group and m is 2 to 4 and R.sup.3.
a) if n is 1 is a radical of formula III in which R.sup.6 and
R.sup.7, which are the same or different, are hydrogen atoms or
methyl, omega-hydroxypropyl or benzyl radicals; or
b) an amino radical of formula IV, in which R.sup.8 is a hydrogen
atom or a methyl radical, R.sup.9 and R.sup.10, which are the same
or different, are hydrogen atoms or methyl, benzyl or phenylethyl
radicals and k is 2, 3 or 4; or
c) a heterocycle of formula V in which R.sup.11 and R.sup.12, which
are the same or different, are hydrogen atoms or methyl radicals, X
is an amino radical of general formula VI, in which R.sup.13 is a
hydrogen atom or a phenyl, benzyl, pyrimidinyl, diphenylmethyl or
phenylethyl radical or X is a radical of formula VII, in which
R.sup.14 is a phenyl radical, R.sup.15 is a cyano or aminomethyl
radical and p and q are 2.
Especially preferred are compounds of formula I wherein R.sup.3 is
one of the following heterocyclic structures: ##STR10## where in Vc
g has the meaning of 0, 1 or 2.
Also preferred are compounds of formula I in which, when n is 1,
R.sup.3 stands for a radical of formula VIII, in which R.sup.9 and
R.sup.10 are methyl radicals and r is 2 or 3 or, when n is 2 or 3,
R.sup.3 is an amino, cyano, hydroxyl, methoxycarbonyl or
carboxamide group.
The present invention also provides a process for the preparation
of the new alkoxy-4(1H)-pyridone derivatives of general formula
(I), wherein either
a) a compound of the formula IX: ##STR11## in which R.sup.1 and
R.sup.2 have the above-given meanings, n is 1 and A is a
nucleofugic group which can be split off, is reacted in known
manner with an amino compound of the formula X, XI or XII:
##STR12## in which R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, k, p, q and X have the above-given meanings;
or
b) a compound of formula XIII: ##STR13## in which R.sup.1 and
R.sup.2 have the above-given meanings and n is 1, is reacted with a
compound of formula XIV: ##STR14## in which R.sup.9, R.sup.10 and r
have the above-given meanings and Y is a group which can be split
off, in an appropriate solvent under basic conditions; or c) when n
is 2 or 3 and R.sup.3 is amino, hydroxyl, cyano, methoxycarbonyl or
caboxamide, a 2-halomethylpyridone of formula IXa: ##STR15## in
which R.sup.1 and R.sup.2 have the above-given meanings and Hal is
a halogen atom, is reacted with a cyanoacetic acid ester in known
manner, saponified and decarboxylated and from the cyano compound
thus obtained of formula Ia: ##STR16## in which R.sup.1 and R.sup.2
have the above-given meanings. An ester, amino, hydroxyl or amido
compound of formula I is prepared according to methods known from
the literature.
The following Scheme I illustrates this latter process.
##STR17##
The reaction according to process a) is carried out in the presence
of an inert solvent, such as methanol, ethanol, propanol or
propan-2-ol and preferably in ethanol or propan-2-ol, at a
temperature of from 20.degree. to 90.degree. C. and preferably of
from 60.degree. to 80.degree. C. The group A which can be split off
is preferably a halogen atom and especially a bromine atom.
In the case of an advantageous embodiment of the nucleophilic
substitution of the residue A in (IX) by the amino compounds used
of formula X, XI and XII, the reaction is carried out in the
presence of a base as acid-binding agent, triethylamine or
potassium carbonate preferably being used. It is possibly
advantageous to use an excess of the amino derivative employed
since it then simultaneously acts as acid-binding agent. The
reaction time is from 1 to 8 hours and is usually from 2 to 3
hours. Purification of the product obtained is carried out in the
usual manner, for example by recrystallization from a solvent,
conversion into an acid-addition salt or column chromatography.
When R.sup.3 in formula I is a heterocycle of the formula Va:
##STR18## a compound of formula IX is first reacted with
4-cyano-4-phenylpiperidine (XIIa) and thereafter the cyano group is
reduced to an aminomethyl radical with Raney nickel and hydrogen.
The reaction is advantageously carried out in an autoclave with
methanol saturated with ammonia at a temperature of from 40.degree.
to 100.degree. C. and preferably of about 60.degree. C. at a
pressure of from 40 to 120 bar and preferably of about 60 bar.
When R.sup.3 in formula I is a heterocycle of formula Vb: ##STR19##
a compound of formula IX is reacted with a piperazine derivative of
formula XIIb: ##STR20## wherein R.sup.16 is a protective group, for
example an ethoxy, methoxy, tert.-butoxy or benzyloxycarbonyl
radical and preferably a methoxycarbonyl radical and the protective
group is subsequently split off. The splitting off of the
protective group takes place according to conventional methods
under acidic conditions. The splitting off of the protective group
R.sup.16 is preferably carried out with hydrogen bromide in glacial
acetic acid in a closed vessel at normal pressure at a temperature
of from 5.degree. to 25.degree. C. and preferably of about
20.degree. C.
In the case of process variant b), the reaction is preferably
carried out in a polar aprotic solvent, for example
dimethylformamide or dimethyl sulphoxide, in the presence of an
appropriate base, preferably sodium hydride (cf. European Patent
Specification No. 0 171 814 which corresponds to U.S. Pat. Nos.
4,603,144, 4,735,964, and 4,812,474). The reaction is carried out
at a temperature of from 20.degree. to 100.degree. C. and
preferably of from 50.degree. to 60.degree. C. Purification of the
product obtained again takes place by recrystallization from a
solvent, conversion into an acid-addition salt or column
chromatography.
The removable group Y of the starting compound of formula XIV can
be a halogen atom, preferably a chlorine or bromine atom and
especially a chlorine atom. Furthermore, as removable groups there
can, for example, also be used aromatic and aliphatic sulphonic
acid residues, for example a p-toluenesulphonic acid or
methanesulphonic acid radical.
In the case of process variant c), the compounds of formula Ia are
prepared by reacting a 2-bromomethylpyridone derivative of formula
IXa, wherein R.sup.1 and R.sup.2 have the above-given meanings,
with tert.-butyl cyanoacetate. The reaction is advantageously
carried out in an inert polar aprotic solvent, preferably in
dimethylformamide, in the presence of a base, preferably of
potassium tert.-butylate, at a temperature of from 20.degree. to
100.degree. C., and preferably of from 50.degree. to 60.degree. C.
The intermediate products thus obtained are subjected to an acidic
or alkaline hydrolysis, an alkyline hydrolysis preferably being
used, for example at ambient temperature in aqueous sodium or
potassium hydroxide solution and methanol. The carboxylic acid
group in the compound obtained is now split off by known methods,
for example by melting or heating in a high boiling solvent.
By catalytic hydrogenation of the cyano group in the compounds of
formula Ia, there are prepared the compounds of formula Ib. The
reaction advantageously takes place in an autoclave with methanolic
ammonia and Raney nickel as catalyst at a temperature of from
40.degree. to 100.degree. C. and preferably of about 60.degree. C.
and at a pressure of from 40 to 120 bar and preferably of about 60
bar.
When, in compounds of formula I, R.sup.3 is a methoxycarbonyl
radical and n is 2, the corresponding cyano compounds of formula Ia
can be reacted with methanolic hydrogen chloride. The reaction is
preferably carried out in a closed vessel at normal pressure and at
ambient temperature with subsequent hydrolysis. By reaction of a
compound of formula Ia with sodium borohydride in boiling
propan-2-ol and subsequent treatment with sodium hydroxide
solution, there are obtained alkoxy-4(1H)-pyridone derivatives of
general formula (Id) and (Ie) (cf, R. A. Egli, Helv. Chim. Acta,
53, 47/1970).
The compounds of formula Ia-Ie can be purified, for example, by
column chromatography, conversion into an acid and/or
recrystallization from a solvent. If desired, the compounds of
formula Ia can be converted into compounds of formula Ie in known
manner by hydrolysis with aqueous or alcoholic alkali metal
hydroxide solutions, for example potassium hydroxide or sodium
hydroxide, at ambient temperature.
If desired, the compounds of formula Ib can be converted into
compounds of formula Id by reduction of the carboxylic acid ester
radical. The reduction can be carried out by generally known
methods, for example with complex metal hydrides, such as sodium
borohydride, in tert.-butanol/methanol (cf. K. Soai, Synthetic
Communications, 12, 463/1982).
The 4(1H)-pyridone derivatives of formulae IX and XIII used as
intermediate products, wherein R.sup.1 and R.sup.2 have the above
given meanings, n is 1 and A is a bromine atom, are prepared from
kojic acid according to processes known from the literature, as
shown by the following reaction Scheme II. ##STR21##
Kojic acid (XVIII) is thereby reacted with an appropriate alkyl
bromide (XIX) according to the usual processes described in the
literature (for example in U.S. Pat. No. 4,644,071; European Patent
Specification No. 0 171 814; A. F. Thomas and A. Marxer, Helv.
Chim. Acta, 43, 469/1960; and European Patent Specification No. 0
209 751 which corresponds to U.S. Pat. No. 4,758,557). This
reaction is preferably carried out with potassium carbonate as base
and dimethylformamide as solvent.
The 2-hydroxymethyl-4-(1H)-pyridone derivatives of formula XIIIa
are prepared by reacting in known manner (cf. for example, Counsell
et al., J. Med. Chem., 17(1), 1-5/1974; J. H. Looker and M. D.
Cliffton, J. Heterocyclic Chem., 23, 5/1986; Tsutomu Teitei, Austr.
J. Chem., 36, 2307-2315/1983; Canadian Patent No. 978,958: S. Hunig
and G. Kubrich, Liebigs Ann. Chem., 609, 181/1958: K. Imafuku et
al., Bull. Chem. Soc. Japan, 52, 107/1979) a pyranone derivative of
formula XX with an amine of formula XXI at a temperature of from
80.degree. to 120.degree. C. and preferably of about 100.degree. C.
In the case of amines with a low boiling point, the reaction is
carried out in an autoclave in the presence of an inert polar
solvent, for example ethanol. The products are purified by column
chromatography or crystallization.
For the conversion of the hydroxymethyl radical in compounds of
formula XIII into a bromoethyl radical, it is especially preferred
to use triphenyl phosphine dibromide, prepared from bromine and
triphenylphosphine (cf. Fieser and Fieser, Reagents for Organic
Synthesis, pub. Wiley-Interscience, 1975, Vol. 5, p. 729). The
reaction is carried out by reacting a solution or suspension of
triphenylphosphine dibromide, prepared in situ, in an appropriate
anhydrous solvent, preferably dichloromethane or toluene, with the
2-hydroxymethyl-4(1H)-pyridone compound of formula XIII in question
at a temperature of from 30.degree. to 100.degree. C. and
preferably at about 50.degree. C. when using dichloromethane as
solvent or at 70.degree. C. when using toluene as solvent. The
2-bromomethyl compounds of formula IXa are isolated after the
reaction as hydrobromides and are purified by crystallization or
further reacted without purification.
Insofar as the compounds according to the present invention of
formula I have a center of chirality, they can be present either as
racemic mixtures or in the form of enantiomers. Racemic mixtures
can be resolved into the enantiomers with the use of conventional
methods.
Since the compounds of formula I possess basic centers, for the
purpose of purification and/or for galenical reasons, they can be
converted with using inorganic or organic acids into crystalline,
pharmacologically acceptable salts. For example, hydrochloric acid,
sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid,
tartaric acid, lactic acid, citric acid, malic acid, salicylic
acid, ascorbic acid, malonic acid, fumaric acid, oxalic acid or
succinic acid can be used. The acid-addition salts are usually
obtained in known manner by mixing the free bases or solutions
thereof with the appropriate acid or a solution thereof in an
organic solvent, for example a lower alcohol, such as methanol,
ethanol or propan-2-ol, or a lower ketone, such as acetone or
butan-2-one, or an ether, such as diethyl ether, diisopropyl ether,
tetrahydrofuran or dioxan.
The compounds of formula I according to the present invention
display useful pharmacological properties. In particular, they
inhibit protein kinase C, a calcium- and phospholipid-dependent key
enzyme, which plays a decisive part in the intracellular signal
chain transduction (Y. Nishizuka, Science, 233, 305-312/1986) and
is closely linked with the regulation of contractile, secretory and
proliferative processes.
On the basis of these properties, the compounds according to the
present invention can be used for the prevention and/or treatment
of heart and blood vessel diseases, such as thromboses,
arterioscleroses and hypertonias, of inflammatory processes,
allergies, cancers and certain degenerative damage of the central
nervous system.
Therefore, the present invention is also concerned with the use of
the alkoxy-4(1H)-pyridone derivatives of formula I for the
treatment of heart and blood vessel diseases, inflammatory
processes, allergies, cancers and diseases of the central nervous
system.
Surprisingly it has been found additionally that the compounds of
formula I according to the present invention induce an
endothelium-dependent smooth muscle relaxation.
The compounds of formula I according to the present invention can
be administered orally or parenterally in liquid or solid form. As
injection medium water is preferably used which contains the
additives usual in the case of injection solutions, such as
stabilizing agents, solubilizing agents or buffers.
Such additives include, for example, tartrate and citrate buffers,
ethanol, complex formers (such as ethylenediamine-tetraacetic acid
and the nontoxic salts thereof), as well as high molecular weight
polymers (such as liquid polyethylene oxide) for viscosity
regulation. Solid carrier materials include, for example, starch,
lactose, mannitol, methyl cellulose, talc, highly dispersed silicic
acids, high molecular weight fatty acids (such as stearic acid),
gelatine, agar-agar, calcium phosphate, magnesium stearate, animal
and vegetable fats and solid high molecular weight polymers (such
as polyethylene glycol). Compositions suitable for oral
administration can, if desired, contain additional flavoring and/or
sweetening agents.
The individual dosages administered enterally or parenterally are
in the range of from 0.5 to 1000 mg and preferably of from 1 to 100
mg.
The following Examples are given for the purpose of illustrating
the present invention.
EXAMPLE 1
2-Hydroxymethyl-5-octadecyloxy-4-pyranone
A mixture of 56.8 g (0.4 mole) kojic acid, 55,3 g (0.4 mole)
potassium carbonate, 133.3 g (0.4 mole) 1-octadecyl bromide, 1 g
potassium iodide and 450 mL anhydrous dimethylformamide is stirred
for 10 hours at 90.degree. C. After cooling, the mixture is mixed
with 1.5 L of water, the precipitate formed is filtered off, well
stirred up once with ethyl acetate, filtered off and recrystallized
from propan-2-ol with the addition of active charcoal. There is
obtained a colorless product: m.p. 71.degree.-73.degree. C.
In a manner analogous to that described in Example 1, there are
obtained the following compounds:
EXAMPLE 2
2-Hydroxymethyl-5-tetradecyloxy-4-pyranone; m.p.
65.degree.-68.degree. C., recrystallized from propan-2-ol.
EXAMPLE 3
5-Eicosanyloxy-2-hydroxymethyl-4-pyranone; m.p.
81.degree.-84.degree. C., recrystallized from propan-2-ol.
EXAMPLE 4
5-Butyloxy-2-hydroxymethyl-4-pyranone
48.3 g (0.352 mole) 1-butyl bromide are added at ambient
temperature, with vigorous stirring, to a mixture of 50 g (0.352
mole) kojic acid, 48.7 g (0.352 mole) potassium carbonate, 1 g
potassium iodide and 420 mL anhydrous dimethylformamide.
Thereafter, the reaction mixture is stirred for 3 hours at
90.degree. C. After cooling, the solvent is removed under vacuum
and the residue is mixed with water and extracted with
dichloromethane. The organic phase is separated off and dried, the
solvent is evaporated and the residue is recrystallized from ethyl
acetate. There is obtained a solid, colorless product; m.p.
68.degree.-73.degree. C.
In a manner analogous to that described in Example 4, there is
obtained the following compound:
EXAMPLE 5
5-Decyloxy-2-hydroxymethyl-4-pyranone; m.p. 46.degree.-50.degree.
C., recrystallized from ethyl acetate.
EXAMPLE 6
2-Hydroxymethyl-5-(9-cis-octadecenyloxy)-4-pyranone
A mixture of 14.2 g (0.1 mole) kojic acid, 13.8 g (0.1 mole)
potassium carbonate, 1 g potassium iodide, 33.14 g (0.1 mole)
1-bromo-9-cis-octadecene and 120 mL anhydrous dimethylformamide is
stirred for 3 hours at 90.degree. C. After cooling, the solvent is
removed under vacuum and the residue is mixed with water and
extracted with dichloromethane. The organic phase is separated off,
dried and evaporated. The residue is purified by column
chromatography on silica gel with dichloromethane-methanol (100:1
v/v) to give a yellow oil, .sup.1 H--NMR (90 MHz; CDCl.sub.3)
(ppm): 0.85 (t, 3H), 1.30 (s, 22H); 1.7-2.2 (m, 6H); 3.8 (t, 2H):
4.2 (t, 1H); 4.4 (d, 2H); 5.3 (t, 2H); 6.5 (s, 1H); 7.55 (s,
1H).
In a manner analogous to that described in Example 6, there are
obtained the following compounds:
EXAMPLE 7
2-Hydroxymethyl-5-(2-octyldecyloxy)-4-pyranone, yellow oil, IR
(KBr): 1640 (C.dbd.O).
EXAMPLE 8
5-[2-(1-Adamantyl)ethoxy]-2-hydroxymethyl-4-pyranon; m.p.
155.degree.-157.degree. C. from 2-propanol/water.
EXAMPLE 9
1-Benzyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone
A mixture of 50.0 g (0.127 mole)
2-hydroxymethyl-5-octadecyloxy-4-pyranone and 70 mL benzylamine is
stirred for 2 hours at 100.degree.-110.degree. C. After cooling to
about 50.degree. C., the dark solution is mixed with 400 mL water
and stirred. The precipitate thus formed is filtered off, washed,
dried and recrystallized from propan-2-ol with thee addition of
active charcoal, colorless crystals thereby being obtained; m.p.
120.degree.-121.degree. C.
In a manner analogous to that described in Example 9, there are
obtained the following compounds:
EXAMPLE 10
1-Benzyl-5-butoxy-2-hydroxymethyl-4(1H)-pyridone; m.p.
123.degree.-124.degree. C., recrystallized from propan-2-ol.
EXAMPLE 11
1-Benzyl-5-decyloxy-2-hydroxymethyl-4(1H)-pyridone; m.p.
128.degree.-129.degree. C., recrystallized from propan-2-ol.
EXAMPLE 12
1-Benzyl-2-hydroxymethyl-5-tetradecyloxy-4(1H)-pyridone; m.p.
121.degree.-123.degree. C., recrystallized from propan-2-ol.
EXAMPLE 13
1-Benzyl-5-eicosanyloxy-2-hydroxymethyl-4(1H)-pyridone; m.p.
120.degree.-122.degree. C., recrystallized from propan-2-ol.
EXAMPLE 14
1-Benzyl-2-hydroxymethyl-5-(9-cis-octadecenyloxy)-4(1H)-pyridone;
m.p. 92.degree.-93.degree. C., recrystallized from ethanol.
EXAMPLE 15
2-Hydroxymethyl-1-(4-methylbenzyl)-5-octadecyloxy-4(1H)-pyridone;
m.p. 122.degree.-125.degree. C., recrystallized from
propan-2-ol.
EXAMPLE 16
1-(4-Chlorobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 125.degree.-127.degree. C., recrystallized from
propan-2-ol.
EXAMPLE 17
2-Hydroxymethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone;
m.p. 120.degree.-122.degree. C., recrystallized from
propan-2-ol.
EXAMPLE 18
2-Hydroxymethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone;
m.p. 107.degree.-110.degree. C., recrystallized from diisopropyl
ether/propan-2-ol.
EXAMPLE 19
1-Cyclohexylmethyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 126.degree.-128.degree. C., recrystallized from
propan-2-ol.
EXAMPLE 20
1-(4-Dimethylaminobenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 109.degree.-114.degree. C., recrystallized from ethanol.
EXAMPLE 21
1-(3-Dimethylaminopropyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 87.degree.-90.degree. C., recrystallized from ethyl
acetate.
EXAMPLE 22
1-(4-Benzyloxybenzyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 116.degree.-120.degree. C., stirred with ether.
EXAMPLE 23
1-Benzyl-2-hydroxymethyl-5-(2-octyldecyloxy-4(1H)-pyridone, yellow
oil, IR (KBr): 1630 (C.dbd.O).
EXAMPLE 24
5-[2-(1-Adamantyl)ethoxy]-1-benzyl-2-hydroxymethyl-4(1H)-pyridone,
Schmp. 246.degree.-248.degree. C., stirred with ether.
EXAMPLE 25
(.+-.)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone
A mixture of 8.0 g (0.02 Mol)
2-hydroxymethyl-5-octadecyloxy-4-pyranone, 4.8 g (0.04 Mol)
(.+-.)-1-phenylethylamine, 1.5 g Na.sub.2 CO.sub.3, 10 mL water and
100 mL ethanol is boiled under reflux for 72 hours. After cooling
the solvent and the excess of amine is removed under vacuum and the
residue is mixed with water and extracted with dichloromethane. The
organic phase is dried over Na.sub.2 SO.sub.4, evaporated and the
obtained resin is purified by column chromatography on silica gel
with dichloromethane with 1-2% methanol to give a yellow oil, which
is changing to wax-like consistency. IR (KBr): 1630 (C.dbd.O), MS
(m/l) 497 (M.sup.+).
In a manner analogous to that described in Example 25, there are
obtained the following compounds:
EXAMPLE 26
(-)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
wax-like, IR (KBr): 1630 (C.dbd.O), [.varies.].sub.D =-15,9.degree.
(C=2.42 methanol).
EXAMPLE 27
(+)-2-Hydroxymethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone,
wax-like, IR (KBr): 1630 (C.dbd.O), [.varies.].sub.D =+16,5.degree.
(C=2.01 methanol).
EXAMPLE 28
2-Hydroxymethyl-5-octadecyloxy-1-propyl-4(1H)-pyridone
A mixture of 20.0 g (51 mMole)
2-hydroxymethyl-5-octadecyloxy-4-pyranone and 30 mL of a 40%
solution of propylamine in ethanol is heated in an autoclave at
100.degree.-110.degree. C. for 5 hours. After cooling, the
crystallizate formed is taken up in water, stirred, filtered off,
dried and recrystallized from ethyl acetate, colorless crystals
thereby being obtained; m.p. 120.degree.-121.degree. C.
In a manner analogous to that described in Example 28, there is
obtained the following compound:
EXAMPLE 29
2-Hydroxymethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone; m.p.
96.degree.-99.degree. C., recrystallized from propan-2-ol.
EXAMPLE 30
2-Hydroxymethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone
5.0 g (12 mMole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone are
suspended in 90 mL water and 2 mL concentrated hydrochloric acid
and mixed with 4.0 g (43 mMole) aniline. The mixture is heated
under reflux for 24 hours, cooled and the precipitate formed is
separated from the aqueous solution and recrystallized from ethyl
acetate, an almost colorless product being obtained; m.p.
67.degree.-72.degree. C.
In a manner analogous to that described in Example 30, there is
obtained the following compound:
EXAMPLE 31
1-(4-Benzyloxyphenyl)-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 68.degree.-70.degree. C.: further worked up in crude form.
EXAMPLE 32
1-Benzyl-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide
5.1 mL (0.1 mole) Bromine are added dropwise at ambient
temperature, while stirring, to a solution of 26.5 g (0.1 mole)
triphenylphosphine in 600 mL anhydrous toluene, a white crystalline
precipitate thereby being formed. After further stirring for 20
minutes at ambient temperature, 48.17 g (0.1 mole)
1-benzyl-2-hydroxymethyl-5-octadecyloxy-4(1H)-pyridone are added
thereto in portions. Thereafter, the reaction mixture is stirred
for 2 hours at 70.degree. C., cooled and the precipitated product
is filtered off, washed with toluene, dried and recrystallized from
propan-2-ol, pale beige crystals being obtained; m.p.
92.degree.-95.degree. C.
In a manner analogous to that described in Example 32, there are
obtained the following compounds:
EXAMPLE 33
1-Benzyl-2-bromomethyl-5-butoxy-4(1H)-pyridone hydrobromide;
syrupy; further worked up in crude form.
EXAMPLE 34
1-Benzyl-2-bromomethyl-5-decyloxy-4(1H)-pyridone hydrobromide;
syrupy; further worked up in crude form.
EXAMPLE 35
1-Benzyl-2-bromomethyl-5-tetradecyloxy-4(1H)-pyridone hydrobomide;
m.p. 135.degree.-137.degree. C., stirred up with acetone.
EXAMPLE 36
1-Benzyl-2-bromomethyl-5-eicosanyloxy-4(1H)-pyridone hydrobromide;
m.p. 97.degree.-100.degree. C., stirred up with acetone.
EXAMPLE 37
1-Benzyl-2-bromomethyl-5-(9-cis-octadecenyloxy)-4(1H)-pyridone
hydrobromide.
EXAMPLE 38
2-Bromomethyl-1-(4-methylbenzyl)-5-octadecyloxy)-4(1H)-pyridone
hydrobromide; m.p. 106.degree.-110.degree. C., recrystallized from
toluene.
EXAMPLE 39
2-Bromomethyl-1-(4-chlorobenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide; m.p. 138.degree.-148.degree. C., stirred up with
toluene.
EXAMPLE 40
2-Bromomethyl-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide; m.p. 94.degree.-97.degree. C., recrystallized from
toluene.
EXAMPLE 41
2-Bromomethyl-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide; further worked up in crude form.
EXAMPLE 42
2-Bromomethyl-1-cyclohexylmethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide; further worked up in crude form.
EXAMPLE 43
2-Bromomethyl-1-(4-dimethylaminobenzyl)-5-octadecyloxy-4(1H)-pyridone
hydrobromide; further worked up in crude form.
EXAMPLE 44
2-Bromomethyl-5-octadecyloxy-1-propyl-4(1H)-pyridone hydrobromide;
m.p. 85.degree.-87.degree. C., recrystallized from acetone.
EXAMPLE 45
2-Bromomethyl-1-methyl-5-octadecyloxy-4(1H)-pyridone hydrobromide;
m.p. 147.degree.-148.degree. C., recrystallized from acetone.
EXAMPLE 46
2-Bromomethyl-5-octadecyloxy-1-phenyl-4(1H)-pyridone hydrobromide;
m.p. 136.degree.-140.degree. C., recrystallized from
propan-2-ol.
EXAMPLE 47
1-(4-Benzyloxybenzyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide, used as crude product.
EXAMPLE 48
1-(4-Benzyloxyphenyl)-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide, used as crude product.
EXAMPLE 49
1-Benzyl-2-bromomethyl-5-(2-octyldecyloxy)-4(1H)-pyridone.multidot.hydrobom
ide
A solution of 0.25 mL (5 mMol) brom in 2.5 mL dichloromethane is
added dropwise at ambient temperature to a solution of 1.3 g (5
mMol) triphenylphosphin in 10 mL dichloromethane while stirring.
The stirring is continued for 20 min and than a solution of 2.4 g
(5 mMol) 2-hydroxymethyl-5-(2-octyldecyloxy)-4-pyranone in 10 mL
dichloromethane is added dropwise. The mixture is boiled under
reflux for 4 hours. After cooling the solvent is distilled off, the
residue mixed with ether, the obtained crystallizate filtered off,
dried and without further purification used.
In a manner analogous to that described in Example 49, there are
obtained the following compounds:
EXAMPLE 50
5-[2-(1-Adamantyl)ethoxy]-1-benzyl-2-bromomethyl-4(1H)-pyridone.multidot.hy
drobromide; m.p. 200.degree.-203.degree. C. from 2-propanol.
EXAMPLE 51
(.+-.)-2-Bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multid
ot.hydrobromide, used as crude product
EXAMPLE 52
(-)-2-Bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multidot.
hydrobromide, used as crude product.
EXAMPLE 53
(+)-2-Bromomethyl-5-octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone.multidot.
hydrobromide, used as crude product.
EXAMPLE 54
1-Benzyl-2-[N-(3-dimethylaminopropyl)-aminomethyl]-5-octadecyloxy-4(1H)-pyr
idone dioxalate
3.1 g (5 mMole)
1-benzyl-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone hydrobromide
are added in portions to a solution of 2.5 g (25 mMole)
3-dimethylamino-1-propylamine in 30 mL propan-2-ol, while stirring
at ambient temperature. The mixture obtained is stirred for 1.5
hours at 60.degree. C., cooled, evaporated under vacuum and the
residue is mixed with water and extracted with dichloromethane. The
dichloromethane solution is dried over anhydrous sodium sulphate,
filtered and evaporated under vacuum to give an oil-like solid
material. This is purified by column chromatography over silica gel
with elution with dichloromethane/ammonia-saturated methanol (9:1
v/v) and then dissolved in methanol. The solution is mixed with a
solution of oxalic acid in methanol and the precipitated salt is
filtered off with suction and recrystallized from methanol/water
(2.5:1 v/v). Colorless crystals being obtained; m.p.
161.degree.-164.degree. C.
In a manner analogous to that described in Example 54, there are
obtained the following compounds:
EXAMPLE 55
1-Benzyl-2-[N-(3-hydroxypropyl)-aminomethyl]-5-octadecyloxy-4(1H)-pyridone;
m.p. 89.degree.-91.degree. C., recrystallized from diisopropyl
ether/propan-2-ol.
EXAMPLE 56
2-[N-(3-Dimethlaminopropyl)-aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyri
done trihydrochloride hemihydrate; m.p. 230.degree. C. (decomp.),
recrystallized from ethanol.
EXAMPLE 57
1-Benzyl-2-[N-(2-dimethylaminoethyl)-N-methylaminomethyl]-5-octadecyloxy-4(
1H)-pyridone trihydrochloride; m.p. 172.degree.-174.degree. C.,
recrystallized from propan-2-ol.
EXAMPLE 58
2-[N-(3-Hydroxypropyl)aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyridone;
m.p. 79.degree.-82.degree. C., digested with diethyl ether.
EXAMPLE 59
2-[N-(3-Dimethylaminopropyl)aminomethyl]-5-octadecyloxy-1-propyl-4(1H)-pyri
done dioxalate; m.p. 171.degree.-172.degree. C., recrystallized
from methanol.
2-[N-(3-Aminopropyl)-aminomethyl]-1-methyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride; m.p. 212.degree.-215.degree. C., recrystallized
from ethanol.
EXAMPLE 61
2-[N-(3-Aminopropyl)-aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride; m.p. 180.degree.-183.degree. C., recrystallized
from ethanol.
EXAMPLE 62
2-[N-(3-Aminopropyl)aminomethyl]-1-propyl-5
-octadecyloxy-4(1H)-pyridone trihydrochloride; m.p.
204.degree.-205.degree. C., recrystallized from
propan-2-ol/methanol.
EXAMPLE 63
1-Benzyl-5-butyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate 3/4 hydrate; m.p. 179.degree.-180.degree. C.,
recrystallized from propan-2-ol.
EXAMPLE 64
1-Benzyl-5-decyloxy-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1H)-pyridone
dioxalate hemihydrate; m.p. 166.degree.-167.degree. C.,
recrystallized from propan-2-ol.
EXAMPLE 65
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-tetradecyloxy-4(1H)-pyr
idone dioxalate monohydrate; m.p. 163.degree.-167.degree. C.
recrystallized from methanol/water.
EXAMPLE 66
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-eicosanyloxy-4(1H)-pyri
done dioxalate monohydrate; m.p. 165.degree. C., recrystallized
from propan-2-ol/water.
EXAMPLE 67
2-[N-(2-Aminoethyl)aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
1/4 hydrate; m.p. 87.degree.-89.degree. C., recrystallized from
diisopropyl ether.
EXAMPLE 68
1-Cyclohexylmethyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecyloxy-
4(1H)-pyridone difumarate; m.p. 142.degree.-145.degree. C.,
recrystallized from ethanol.
EXAMPLE 69
1-(4-Chlorobenzyl)-2-[N-(3-dimethylamino-propyl)aminomethyl]-5-octadecyloxy
-4(1H)-pyridone difumarate 1.25 hydrate; m.p.
121.degree.-123.degree. C., recrystallized from ethanol.
EXAMPLE 70
2-[N-(3-Dimethylaminopropyl)aminomethyl]-5-octadecyloxy-1-phenyl-4(1H)-pyri
done; diisopropyl ether.
EXAMPLE 71
1-Benzyl-2-[N-(3-N-benzyl-N-methylaminopropyl)aminomethyl]-5-octadecyloxy-4
(1H)-pyridone difumarate; m.p. 140.degree.-142.degree. C.,
recrystallized from ethanol.
EXAMPLE 72
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone trihydrochloride monohydrate; m.p.
140.degree.-145.degree. C., recrystallized from
butan-2-one/propan-2-ol.
EXAMPLE 73
1-Benzyl-2-dimethylaminomethyl-5-octadecyloxy-4(1H)-pyridone
oxalate hemihydrate; m.p. 138.degree.-139.degree. C.,
recrystallized from propan-2-ol.
EXAMPLE 74
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(2-methoxybenzyl)-5-octadecyloxy
-4(1H)-pyridone difumarate; m.p. 108.degree.-112.degree. C.,
recrystallized from propan-2-ol.
EXAMPLE 75
1-Benzyl-2-(N-benzyl-N-methylaminomethyl)-5-octadecyloxy-4(1H)-pyridone;
m.p. 59.degree.-61.degree. C., recrystallized from ligroin.
EXAMPLE 76
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-methylbenzyl)-5-octadecyloxy-
4(1H)-pyridone trihydrochloride hemihydrate; m.p.
141.degree.-148.degree. C., recrystallized from ethyl
acetate/propan-2-ol.
EXAMPLE 77
2-[N-(4-Aminobutyl)aminomethyl]-1-benzyl-5-octadecyloxy-4(1H)-pyridone
trihydrochloride; m.p. 179.degree.-183.degree. C., recrystallized
from diethyl ether/ethyl acetate.
EXAMPLE 78
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(9)-cis-octadecenyloxy)
-4(1H)-pyridone.multidot.trihydrochloride.multidot.1/2 H.sub.2 O;
m.p. 181.degree.-185.degree. C. from ethyl acetate.
EXAMPLE 79
1-(4-Benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone; m.p. 43.degree.-47.degree. C.
EXAMPLE 80
1-(4-Benzyloxyphenyl)-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-octadecylo
xy-4(1H)-pyridone.multidot.difumarate.multidot.2,5 H.sub.2 O; m.p.
103.degree.-109.degree. C. from 2-propanol/ethyl acetate.
EXAMPLE 81
1-Benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-5-(2-octyldecyloxy)-4(1H)
-pyridone.multidot.trihydrochloride.multidot.3/4 H.sub.2 O; m.p.
168.degree.-172.degree. C. from methylethylketon/2-propanol.
EXAMPLE 82
5-(2-Adamantylethoxy)-1-benzyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-4(1
H)-pyridone, yellow oil, MS (m/l) 477 M.sup.+.
EXAMPLE 83
(.+-.)-1-Benzyl-5-octadecyloxy)-2-{N-[3-(1-phenylethyl)aminopropyl]-aminome
thyl}-4(1H)-pyridone.multidot.trihydrochloride; m.p.
125.degree.-127.degree. C. mixed with toluene.
EXAMPLE 84
2-[N-(3-Dimethylaminopropyl)-aminomethyl[-1-(4-hydroxybenzyl)-5-octadecylox
y-4(1H)-pyridone.multidot.dihydrochloride.multidot.2 H.sub.2 O
To a solution 1.0 g (1.5 mMol)
1-(4-benzyloxybenzyl)-2[N-(3-dimethylaminopropyl)aminomethyl]-5-octadexylox
y-4(1H)-pyridone in 30 mL absolute ethanol are added 0.25 g
palladium on charcoal (10% ig, oxide-type) and the mixture is
hydrogenated at ambient temperature and normal pressure. After
filtration of the catalyst the solvent is distilled off and the
residue purified by column chromatography on silica gel with
dichloromethane with 3-6% methanol saturated with gaseous NH.sub.3.
gesattigt saulenchromatographiert. The obtained reaction product
(was-like compound with R.sub.f =0,55, silica gel,
dichloromethan/methanol, saturated with NH.sub.3 4:1) is mixed with
methanol, saturated with gaseous HCl, to obtain the salt form. The
solvent is distilled off and the residue recrystallized from
2-propanol/ethyl acetate. There are obtained colorless crystals;
m.p. 153.degree.-156.degree. C.
In a manner analogous to that described in Example 84, there is
obtained the following compound:
EXAMPLE 85
2-[N-(3-Dimethylaminopropyl)aminomethyl]-1-(4-hydroxyphenyl)-5-octadecyloxy
-4(1H)-pyridone.multidot.trihydrochloride.multidot.0,5 H.sub.2 O;
m.p. 236.degree.-237.degree. C. from methanol.
EXAMPLE 86
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-cyano-4-phenylpipe
ridine dihydrochloride
A solution of 2.0 g (9 mMole) 4-cyano-4-phenylpiperidine
hydrochloride in 40 mL ethanol is mixed with 4.8 mL (35 mMole)
triethylamine. 5.0 g (8 mMole)
1-benzyl-2-bromomethyl-5-octadecyloxy-4 (1H)-pyridone hydrobromide
are added in portions to this mixture, while stirring at ambient
temperature. The reaction mixture is stirred for 3 hours at
60.degree. C., the solvent is removed under vacuum, the residue is
mixed with water and dichloromethane, stirred and the organic phase
is separated off, dried over anhydrous sodium sulphate and
evaporated. The residue is purified by column chromatography on
silica gel with dichloromethane/methanol (97:3 v/v). There is
obtained an oily product. 1.0 g (1.5 mMole) of this substance is
dissolved in 30 mL ethyl acetate and mixed with diethyl ether
saturated with gaseous hydrogen chloride for salt formation. The
precipitated salt is recrystallized from ethyl acetate/propan-2-ol
(6:1 v/v), colorless crystals being obtained (m.p.
106.degree.-112.degree. C.). The solid material contains about 3/4
mole of water per mole of the said product.
In a manner analogous to that described in Example 86, there are
obtained the following compounds:
EXAMPLE 87
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-methoxycarbonyl-2-
methyl-piperazine dihydrochloride 3/4 hydrate; m.p.
111.degree.-117.degree. C., recrystallized from ethyl
acetate/propan-2-ol.
EXAMPLE 88
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-benzylpiperazine;
m.p. 78.degree.-80.degree. C., recrystallized from diisopropyl
ether.
EXAMPLE 89
1-Benzyl-2-[N-(3-dimethylaminopropyl)-N-methylaminomethyl]-5-octadecyloxy-4
(1H)-pyridone trihydrochloride; m.p. 186.degree.-189.degree. C.,
recrystallized from propan-2-ol/ethanol.
EXAMPLE 90
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-diphenylmethylpipe
razine sesquioxalate monohydrate; m.p. 124.degree.-129.degree. C.,
recrystallized from ethyl acetate.
EXAMPLE 91
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-phenylpiperazine.
multidot.dihydrochloride.multidot.H.sub.2 O; m.p. 80.degree. C.
(sintering) from ethyl acetate/methanol.
EXAMPLE 92
1-[1-Benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-(2-pyrimidinyl)pip
erazine; m.p. 96.degree.-97.degree. C. from
diisopropylether/2-propanol.
EXAMPLE 93
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-benzylpiperazine.
multidot.dioxlate.multidot.1/2 H.sub.2 O; m.p.
133.degree.-136.degree. C. from ethanol.
EXAMPLE 94
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridone-2-yl)methyl]-4-(2-phenylethyl)pi
perazine.multidot.trihydrochloride.multidot.1/2 H.sub.2 O; m.p.
161.degree.-164.degree. C. from ethylacetate/2-propanol.
EXAMPLE 95
1-[(1-Benzyl-5-decyloxy-4(1H)-pyridone-2-yl)-methyl]4-(2-phenylethyl)pipera
zine.multidot.dihydrochloride; m.p. 161.degree.-164.degree. C. from
ethylacetate/2-propanol.
EXAMPLE 96
1-[(1-Benzyl-5-benzyloxy-4(1H)-pyridone-2-yl)-methyl]-4-benzylpiperazine.mu
ltidot.trihydrochloride; m.p. 189.degree.-191.degree. C. from
ethylacetate/2-propanol.
EXAMPLE 97
(.+-.)-1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridone-2
-yl)methyl]-4-(1-phenylethyl)piperazine.multidot.trihydrochloride
3/4 H.sub.2 O; m.p. 167.degree.-170.degree. C. from
acetonitrile/2-propanol.
EXAMPLE 98
(.+-.)-1-[(5-Octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone-2-yl)-methyl]-4-
benzylpiperazine; m.p. 76.degree.-78.degree. C. from
diisopropylether.
EXAMPLE 99
(-)-1-[(5-Octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone-2-yl)-methyl]-4-ben
zylpiperazine; m.p. 60.degree.-61.degree. C. from diisopropylether,
[.varies.].sub.D =-2,3.degree. (C=2,06 methanol).
EXAMPLE 100
(+)-1-[(5-Octadecyloxy-1-(1-phenylethyl)-4(1H)-pyridone-2-yl)-methyl]-4-ben
zylpiperazine; m.p. 60.degree.-61.degree. C. from diisopropylether,
[.varies.].sub.D =+2,4.degree. (C=2,01 methanol).
EXAMPLE 101
1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-4-aminomethyl-4-phen
ylpiperidine trihydrochloride
2.7 g (4.1 mMole)
1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)-methyl]-4-cyano-4-phenylpi
peridine are mixed with 60 mL methanol saturated with gaseous
ammonia and 1 g Raney nickel and hydrogenated with hydrogen in an
autoclave at 60.degree. and 60 bar pressure. After 6 hours, the
reaction is finished. After filtering off the catalyst with
suction, the pale yellow solution obtained is evaporated under
vacuum and the residue chromatographed on a column of silica gel
with dichloromethane/methanol saturated with ammonia (97:3 v/v).
The reaction product thus obtained (oily substance with the R.sub.f
=0.5, silica gel, dichloromethane/methanol saturated with ammonia
(9:1 v/v) is dissolved in ethyl acetate and mixed with diethyl
ether saturated with gaseous hydrogen chloride for salt formation.
The precipitated salt is recrystallized from
butan-2-one/propan-2-ol (10:1 v/v), colorless crystals being
obtained; m.p. 192.degree.-197.degree. C. The solid material
contains about 1.25 mole of water per mole of the said product.
EXAMPLE 102
(.+-.)-1-[(1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)methyl]-2-methylpiper
azine fumarate
A mixture of 2 g (3.2 mMole)
(35)-1-[(1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl)-methyl]-4-methoxycarb
onyl-2-methylpiperazine, 5 mL 33% hydrogen bromide/acetic acid and
5 mL acetic acid is stirred for 2 hours in a closed vessel. After
stripping off the main amount of the solvent under vacuum, the
residue is mixed with water, rendered alkaline with a 2N aqueous
solution of sodium hydroxide and extracted with dichloromethane.
The organic phase is separated off, dried over anhydrous sodium
sulphate and evaporated. The resin obtained is purified by
chromatography on a column of silica gel with
dichloromethane/methanol saturated with gaseous ammonia (96:3 v/v).
The reaction product thereby obtained (oily substance with the
R.sub.f =0.2; silica gel, dichloromethane/methanol saturated with
gaseous ammonia 9:1 v/v) is dissolved in propan-2ol and mixed with
a solution of fumaric acid in propan-2-ol. After standing for 24
hours, the clear solution is evaporated and the salt is
recrystallized from butan-2-one, colorless crystals being obtained;
m.p. 151.degree.-155.degree. C. The solid material contains about 1
mole of water per mole of the said product.
EXAMPLE 103
1-Benzyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-pyridone
dihydrochloride
7.2 g (15 mMole)
1-Benzyl-2-hydroxymethoxy-5-octadecyloxy-4(1H)-pyridone are
dissolved in 110 mL anhydrous dimethylformamide at 70.degree. C.
and mixed portionwise with 0.60 g (20 mMole) sodium hydride (80% in
paraffin oil). After subsequently stirring for 1.5 hours at
70.degree. to 80.degree. C., a solution of 3.3 g (27.15 mMole)
3-dimethylaminopropyl chloride in 20 mL anhydrous dimethylformamide
is added dropwise thereto. The reaction mixture is then stirred for
2 hours at 70.degree. C. Thereafter, the solution is evaporated to
dryness under vacuum and the residue is mixed with water and
dichloromethane. The organic phase is separated off, dried over
anhydrous sodium sulphate and evaporated. The residue is
chromatographed on a column of silica gel with
dichloromethane/methanol saturated with gaseous ammonia (97:3 v/v),
an oily substance being obtained. 1.8 g (3.3 mMole) of this
substance are dissolved in a mixture of 30 mL ethyl acetate and 3,5
mL propan-2-ol and mixed with diethyl ether saturated with gaseous
hydrogen chloride for salt formation. The precipitated salt is
recrystallized from ethyl acetate/propan-2-ol (3:1 v/v), colorless
crystals being obtained; m.p. 155.degree.-159.degree. C. The solid
material contains about 1/4 mole of water per mole of the said
product.
In a manner analogous to that described in Example 103, there are
obtained the following compounds:
EXAMPLE 104
2-(3-Dimethylaminopropoxymethyl)-1-methyl-5-octadecyloxy-4(1H)-pyridone
dihydrochloride; m.p. 210.degree.-216.degree. C., recrystallized
from propan-2-ol.
EXAMPLE 105
2-(3-Dimethylaminopropoxymethyl)-5-octadecyloxy-1-propyl-4(1H)-pyridone
dihydrochloride 3/4 hydrate; m.p. 127.degree.-128.degree. C.,
recrystallized from ethyl acetate/propan-2-ol.
EXAMPLE 106
2-(3-Dimethylaminopropoxymethyl)-1-(4-methylbenzyl)-5-octadecyloxy-4(1H)-py
ridone dihydrochloride sesquihydrate; m.p, 87.degree.-84.degree.
C., recrystallized from ethyl acetate/propan-2-ol.
EXAMPLE 107
2-(3-Dimethylaminopropoxymethyl)-1-(4-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone dihydrochloride 1/4 hydrate; m.p. 144.degree.-147.degree.
C., recrystallized from propan-2-ol.
EXAMPLE 108
1-Cyclohexylmethyl-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone oxalate; m.p. 81.degree.-84.degree. C., recrystallized from
ethyl acetate/l propan-2-ol.
EXAMPLE 109
1-(4-Chlorobenzyl)-2-(3-dimethylaminopropoxymethyl)-5-octadecyloxy-4(1H)-py
ridone dihydrochloride 2.5 hydrate; m.p. 70.degree.-74.degree. C.,
recrystallized from ethyl acetate/propan-2-ol.
EXAMPLE 110
2-(3-Dimethylaminopropoxymethyl)-1-(2-methoxybenzyl)-5-octadecyloxy-4(1H)-p
yridone sesquihydrate; m.p. 89.degree.-91.degree. C.,
recrystallized from ethyl acetate/propan-2-ol.
EXAMPLE 111
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propionic acid
nitrile hydrochloride
A. tert.-Butyl
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-2-cyanopropionate
A solution of 21.2 g (0.15 mole) tert.-butyl cyanoacetate in 15 mL
anhydrous dimethylformamide is added dropwise at ambient
temperature, while stirring, to a solution of 17.0 g (0.15 mole
potassium tert.-butylate in 60 mL anhydrous dimethylformaide. The
clear solution is warmed to 50.degree. C. and a solution of 43.4 g
(0.07 mole) 1-benzyl-2-bromomethyl-5-octadecyloxy-4(1H)-pyridone
hydrobromide in 150 mL anhydrous dimethylformamide added thereto at
this temperature in the course of 5 minutes. After stirring for 1
hour at 55.degree. C., the reaction mixture is added to 1.2 L of
water and extracted with ethyl acetate. The organic phase is
separated off, dried over anhydrous sodium sulphate and evaporated.
The oily residue is purified by chromatographing on a column of
silica gel with dichloromethane/methanol (9.1 v/v) (R.sub.f =0.60;
silica gel, dichloromethane/methanol 9:1 v/v), a yellow, oily
product being obtained.
B. 3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-2-cyanopropionic
acid
13.2 g (22 mMole) tert.-butyl
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-3-yl]-2-cyanopropionate
are mixed with 47 mL 0.5N potassium hydroxide in methanol and
stirred for 3 days at ambient temperature. The solvent is removed
under vacuum and the residue is dissolved in water and acidified
with 2N hydrochloric acid. The precipitate obtained is filtered off
with suction, washed with water and diethyl ether and dried, a
solid, colorless product being obtained (m.p.
122.degree.-124.degree. C.) which is sufficiently pure for the
further reaction.
C. 3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile hydrochloride
4.1 g (7.4 mMole)
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-2-cyanopropionic
acid are heated to 150.degree. C. for 30 minutes. After cooling,
the product is obtained as an oil which is sufficiently pure for
the further reaction.
0.5 g (1 mMole) of the substance is dissolved in ethyl acetate and
mixed with diethyl ether saturated with gaseous hydrogen chloride
for salt formation. The precipitated salt is filtered off with
suction and dried, a beige product being obtained; m.p.
98.degree.-102.degree. C.
In a manner analogous to that described in Example 111, there is
obtained the following compound:
EXAMPLE 112
3-(1-Methyl-5-octadecyloxy-4(1H)-pyridon-2-yl)propionic acid
nitrile; m.p. 85.degree.-87.degree. C., digested with diethyl
ether.
EXAMPLE 113
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]propylamine
dihydrochloride
3.7 g (7.3 mMole)
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile are mixed with 40 mL methanol saturated with gaseous
ammonia and hydrogenated with hydrogen at 60.degree. C. and 60 bar
in an autoclave. After filtering off the catalyst, the solution is
evaporated under vacuum and the oily residue chromatographed on a
column of silica gel with dichloromethane/methanol saturated with
ammonia (95:5 v/v). There are thus obtained 2.2 g (59% of theory)
of oil substance (R.sub.f =0.1, silica gel,
dichloromethane/methanol saturated with ammonia 9:1 v/v) which is
converted with ethereal hydrochloric acid into the hydrochloride
which is then recrystallized from butan-2-one/propan-2-ol (4:1
v/v), colorless crystals being obtained; m.p.
138.degree.-143.degree. C.
EXAMPLE 114
Methyl
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionate
3.0 g (6 mMole)
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile are dissolved in 30 mL methanol saturated with gaseous
hydrogen chloride and left to stand for 3 days at ambient
temperature in a closed vessel. After stripping off the solvent
under vacuum, the residue is mixed with water, rendered alkaline
with a dilute aqueous solution of sodium hydroxide and extracted
with dichloromethane. The dichloromethane solution is dried over
anhydrous sodium sulphate and evaporated. The wax obtained is
recrystallized twice from diisopropyl ether, colorless crystals
being obtained; m.p. 78.degree.-81.degree. C.
EXAMPLE 115 AND 116
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propanol and
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
amide
5.0 g (10 mMole)
3-[1-Benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid
nitrile in 30 mL propan-2-ol are mixed, while stirring at ambient
temperature, with 2.5 g (6.6 mMole) sodium borohydride and the
reaction mixture further stirred for 4 days at 80.degree. C. After
stripping off the solvent under vacuum, the residue is mixed with a
dilute aqueous solution of sodium hydroxide and stirred for 30
minutes at 40.degree. C. After cooling, it is extracted with
dichloromethane, the organic phase is washed with water, dried and
evaporated. The residue is chromatographed on a column of silica
gel with dichloromethane/methanol. By elution with dichloromethane
containing 1 to 5% methanol, there is obtained the crude
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propanol (R.sub.f
=0.30; silica gel, dichloromethane/methanol 9:1 v/v). After
recrystallization from diisopropyl ether/propan-2-ol (4:1 v/v),
there are obtained pale beige crystals; m.p. 87.degree.-89.degree.
C.
By further elution of the column with dichloromethane containing 6
to 10% methanol, there is obtained crude
3-[1-benzyl-5-octadecyloxy-4(1H)-pyridon-2-yl]-propionic acid amide
(R.sub.f =0.40: silica gel; dichloromethane/methanol 9:1 v/v).
After recrystallization from butan-2-one, there are obtained
colorless crystals; m.p. 134.degree.-136.degree. C.
Inhibition of the activity of protein kinase C
For the clarification of the inhibiting influence of compounds of
formula I according to the present invention on the calcium- and
phospholipid-dependent protein kinase (PKC), this enzyme activity
was enriched from rat brain. Using the purification steps described
in the literature (J. Biol. Chem., 260, 15718-15722/1985), in the
case of a purification consisting of two steps, there was utilized
the property of the enzyme to bind to cell membranes in the
presence of calcium and to be dissolved off again by calcium
chelators (EGTA). In the first enrichment step, there took place
the binding of the PKC to membranes of the rat brain and in the
second step on so-called inside-out vesicles or erythrocytes. After
dissolving off from the erythrocyte membranes and rebuffering, the
PKC preparation was present in 10 mM HEPES, 1 mM DTT, 0.1% PEG
20000, pH 7.5. Under these conditions, it could be stored at
-70.degree. C. for several months without loss of activity.
The activity of the enzyme was determined via the incorporation of
P.sup.32 -labelled phosphate into the protein histone H-1 (Sigma
Type III) which can be phosphorylated by PKC.
The test thereby contains the following components: 50 mM
HEPES-NaOH (pH 7.5), 5 mM magnesium chloride, 1 mM DTT, 4 .mu.m.
free calcium ions, 10 .mu.MaTP, 1 .mu.g phosphatidylserine, 0.2
.mu.g 1,2-diolein, as well as 40 .mu.g histone H-1 and optionally
the test substance.
The batch is preincubated for 4 minutes at 30.degree. C. and the
reaction then started by the addition of 5 nM PKC. After incubating
for 5 minutes at 30.degree. C., the reaction is stopped with 10%
TCA and the samples then filtered off. The phosphate incorporation
is determined by Cerenkov counting in a scintillation counter. The
kinase activity measured in the absence of the test substance was,
in each case, taken as being 100% and the inhibiting action of the
compounds of formula I referred thereto as percentages. The results
obtained are set out in the following Table I.
Endothelium-dependent smooth muscle relaxation
Rabbit aorta rings are fixed in an organ bath filled with
physiological salt solution (Krebs-Henseleit) between L-shaped
wires. The solution is gassed with carbogen. Contractions are
initiated by 3.times.10.sup.-7 noradrenaline. When the tension has
reached a stable plateau, compounds of the instant invention are
added. The effect of the compounds first is tested on organ
preparation with functioning endothelium. In an additional
experiment in order to test whether the relaxation is
endothelium-dependent the compounds are tested with aorta rings
with damaged endothelium. For an endothelium-dependent relaxation,
effected by the endothelium-derived relaxating factor (EDRF), the
following characteristics are required: absence of the effect in
preparations with damaged endothelium, no inhibition of the
relaxation by indomethazine and inhibition of the relaxation by
NDGA (nordihydro-guaiaretic acid), methylene blue and gossypol.
These criteria are completely met by the compounds listed in Table
II, and one can conclude, that the compounds of the instant
invention act in an unexpected manner by the release of EDRF, and
thereby relax vascular smooth muscle.
TABLE I ______________________________________ Inhibition of
Protein Kinase C Example No. IC.sub.50 (mol/mL)
______________________________________ 21 2.4 .times. 10.sup.-6 54
1.4 .times. 10.sup.-6 56 2.9 .times. 10.sup.-6 57 1.9 .times.
10.sup.-6 59 2.9 .times. 10.sup.-6 60 2.7 .times. 10.sup.-6 61 2.1
.times. 10.sup.-6 65 6.5 .times. 10.sup.-6 66 2.5 .times. 10.sup.-6
68 1.9 .times. 10.sup.-6 69 1.5 .times. 10.sup.-6 70 2.2 .times.
10.sup.-6 71 1.8 .times. 10.sup.-6 72 3.6 .times. 10.sup.-6 73 4.4
.times. 10.sup.-6 74 2.1 .times. 10.sup.-6 75 9.5 .times. 10.sup.-6
76 1.9 .times. 10.sup.-6 77 2.3 .times. 10.sup.-6 78 4.6 .times.
10.sup.-6 79 2.2 .times. 10.sup.-6 80 2.6 .times. 10.sup.-6 83 2.6
.times. 10.sup.-6 84 3.4 .times. 10.sup.-6 85 5.8 .times. 10.sup.-6
88 3.0 .times. 10.sup.-6 89 1.8 .times. 10.sup.-6 93 5.5 .times.
10.sup.-6 94 2.4 .times. 10.sup.-6 95 4.3 .times. 10.sup.-6 97 4.4
.times. 10.sup.-6 98 5.4 .times. 10.sup.-6 99 5.2 .times. 10.sup.-6
100 2.7 .times. 10.sup.-6 101 1.5 .times. 10.sup.-6 102 2.0 .times.
10.sup.-6 103 4.0 .times. 10.sup.-6 105 2.0 .times. 10.sup.-6 106
2.4 .times. 10.sup.-6 107 2.9 .times. 10.sup.-6 108 2.9 .times.
10.sup.-6 109 2.6 .times. 10.sup.-6 114 9.0 .times. 10.sup.-6 116
9.0 .times. 10.sup.-6 ______________________________________
TABLE II ______________________________________ Relaxation of
Noradrenaline-Precontracted Aorta (3 .times. 10.sup.-7 mol/L);
EC.sub.50 ; mol/L Functioning Damaged Example No. Endothelium
Endothelium ______________________________________ 54 1.5 .times.
10.sup.-5 >10.sup.-4 101 2 .times. 10.sup.-5 >10.sup.-4 69 3
.times. 10.sup.-5 >10.sup.-4 71 3 .times. 10.sup.-6
>10.sup.-4 88 3.4 .times. 10.sup.-6 >10.sup.-4 Acetylcholine
3 .times. 10.sup.-8 >10.sup.-4
______________________________________
* * * * *